Nortropine derivatives



United States Patent 3,470,187 NORTROPINE DERIVATIVES Stephen I. Sallay,Wynnewood, and Scott J. Childress,

Philadelphia, Pa., assignors to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware No Drawing. Filed May 24, 1967,Ser. No. 640,849 Int. Cl. C07d 39/00; A61k 27/00 US. Cl. 260292 2 ClaimsABSTRACT OF THE DISCLOSURE Piperidine and tropane derivatives having anolefinic component in the 3 or 4-position of the ring have beenprepared, the compounds demonstrating a central nervous systemstimulating action.

Background of the invention The invention pertains to a class ofnitrogen-containing heterocyclic compounds more particularly piperidineand tropane derivatives having pharmacological activity.

The prior art discloses numerous piperidine derivatives mainly havingpharmodynamic activity in the field of analgesics. The art also teachesthe preparation of a number of tropane derivatives characterized by thetypical action of these substances, essentially parasympatholytic innature.

The state of the art known to the applicants may be represented by thefollowing patents identified by US. Patents Nos. 2,739,969; 2,800,479;2,947,753; 3,056,795; and 3,056,796.

Summary The invention relates to the preparation of novel piperidinederivatives and closely related nortropane compounds with the object offinding compounds possessing valuable pharmacological properties.

Unexpected pharmacological action was found in a group of 3 or4-substituted piperidine and nortropine compounds in which thesubstituent was an olefinic radical. The compounds showed activity ascentral nervous system stimulants and are therefore useful in the fieldof experimental and comparative pharmacology. In addition to theanti-depressant action, anti-inflammatory and analgesic action was alsonoted.

Description of the invention The compounds of the invention areillustrated by the following structural embodiment:

Rs-N

In the above structure, X and Y are intended to represent either CH orthe symbol C=CR R but both are dissimilar in that when X is one symbol,Y is the other. The radical =CR R is intended to represent either adi-halo methylene radical or a lower alkyl ester radical. The radical Ris intended to represent either a lower alkyl, preferably methyl or aphenyl(lower)alkyl, preferably phenethyl, while the radicals R and Rrepresent either hydrogen or when taken together represent a divalentethylene bridge between the ring carbons adjacent to the nitrogen atomto form a tropane configuration or bicyclic structure.

Compounds of the piperidine type, namely, where R and R in the aboveformula are hydrogen and having a dihalogen methylene radical, areprepared by first reacting a trihalomethane with triphenylphosphine andpotassium t-butoxide in a hydrocarbon solvent, preferably heptane.

The reaction product is concentrated by heating and is then reacted withN-substituted-3 or 4-piperidone to form the correspondingN-substituted-dihalo-methylene piperidine. Instead of carrying out thefinal reaction step with a 3 or 4-piperidone, it is contemplated tocarry out the reaction with an N-substituted-nortropane-3-one in whichcase the final product is an N-substituted-3 dihalomethylene-nortropane.

In order to prepare compounds of the invention having an acetic acidalkyl ester radical in the 3 or 4-position of the piperidine ornortropane ring, a tri(lower)alkyl phosphonoacetate, but preferablytriethylphosphonoacetate, is reacted with sodium hydride in a solvent,preferably ethyleneglycol dimethylether (monoglyme). The reaction iskept below about 30 C. After action is completed, the mixture is reactedwith the selected piperidone or nortropanone at about room temperatureand the desired product is separated.

The compounds of the invention are useful either as the free bases or aseither acid-addition salts or quaternary ammonium compounds.

The salts are formed by reacting the bases in known manner with organicor inorganic acids capable of forming pharmaceutically acceptableacid-addition salts. Suggested acids are, for example, acetic, citric,tartaric, maleic, or oxalic acids, among usual acids used to formnon-toxic acid-addition salts. Inorganic acids are also contemplated andamong these the hydrohalides, for example hydrochloride or bromide,sulfuric or phosphoric acids are useful for this purpose.

As indicated, quaternary ammonium salts may be formed in known mannerfrom the bases described, using for example, a lower alkyl halidereactant, preferably methyl chloride, bromide or iodide. These also formsalts that are non-toxic in the dosage range contemplated.

The compounds are used directly but more preferably in composition format a dosage range of 10 to 150 mg./ kg. Within this range thepharmacological action and medicinal utility as central nervous systemstimulants is clearly demonstrated.

Medically useful compositions may be prepared for oral or parenteraluse, containing a compound of the invention either alone or with othersimilarly active substances. Oral compositions may be in the form oftablets or capsules, or in liquid form with an aqueous carrier. In

preparing tablets or capsules conventional and well known carriers orexcipients are used such as lactose, starch, talc or calcium carbonate,together with usual tabletting materials such as magnesium stearate.Oral liquid forms may contain solid suspending agents particularly ifsparingly soluble active ingredients are used. Parenteral compositionsin aqueous form may also be prepared by combining soluble salts of theactive substances in an aqueous medium.

The following examples are given for illustrative purposes in teachinghow to carry out the inventive concept. It is to be understood that thetemperatures are in degrees centigrade.

EXAMPLE 1 Chloroform (12.0 g.) in 200 ml. of n-heptane was added over 30minutes to a stirred, ice-cooled mixture of triphenylphosphine (26.2 g.)and potassium-t-butoxide (11.5 g.) in 250 ml. of heptane. The yellowcolored suspension was concentrated to about ml. at 15-20. ThenN-methyl-4-piperidone (11.3 g.) in 100 ml. heptane was added within 15minutes. The mixture was heated to 40-50 for A. hour and finally it washeated to 70 and allowed to stand over-night at room temperature. Thereaction mixture was filtered and the filter cake was Washed with 2X 100ml. of heptane. The combined heptane solution was evaporated to drynessand the yellow 3 oily residue was distilled at 46/0.1 mm. The free base4-dichloromethylene-l-methylpiperidine gave a maleate salt fromethanol-ether; M.P. 136138.

EXAMPLE 2 The same reaction as Example 1 is carried out but using 25.3g. of bromoform in place of the chloroform reactant. The product formedis the free base, dibromomethylene-l-methylpiperidine.

EXAMPLE 3 Following the procedure of Example 1 but using N-benzyl-3-piperidone instead of N-methyl-4-piperidone, 1-benzyl-3-dichloromethylenepiperidine was obtained. The oxalate of1-benzyl-3-dichloromethylenepiperidine was recrystallized frommethanol-ether, M.P. 176l77.

EXAMPLE 4- Instead of using N-benzyl-3-piperidone as in Example 3 useN-phenethyl-3-piperidone and follow the process of Example 1, to producethe free base, 1-phenethyl-3-dichloromethylenepiperidine.

EXAMPLE 5 Following the procedure of Example 1, but using tropinone asan aminoketone, 3-dichloromethylene-8- methylnortropane was obtained andcharacterized as a citrate salt; M.P. 1735-1745 (from ethanol.)

EXAMPLE 6 ture. The unreacted tropinone was separated by forming itsoxime by hydroxylamine acetate in boiling methanol (1 hr. reflux). Thereaction mixture was evaporated, dissolved in a minimum amount ofchloroform and chromatographed on A1 0 column. Chloroform eluated A-tmpane acetic acid ethylester as a yellow oil which was transformedinto the citrate salt; M.P. 114-1155 (from acetone-ether).

In place of using triethylphosphonoacetate, an equivalent molar amountof trimethylphosphonoacetate may be used to form the A --tropane aceticacid methyl ester base. This, and various other obvious changes may bemade in carrying out the invention without departing from the spirit orscope thereof.

The invention being claimed is:

1. A compound of the group consisting of a base having the formula:

in which R is selected from the group consisting of lower alkyl andphenyl(lower)alkyl; and the pharmaceutically acceptable acid-additionsalts thereof.

2. As a compound of claim 1, 3-dichloromethylene-8- methylnortropine.

References Cited Calvert et al.: J. Chem. Soc., London, 1965, pp.2723-7.

HENRY R. JILES, Primary Examiner A. L. ROTMAN, Assistant Examiner US.Cl. X.R. 260-293, 294.3, 999

